TuberculosisPhase 3Doxy-TBNCT05473520
Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis
A Phase 3 study testing Doxycycline in people with Tuberculosis and Acute Coronary Syndrome, run by National University Hospital, Singapore at 6 sites in 2 countries.
Trial summary
Tuberculosis (TB) is a global pandemic that despite successful treatment and bacterial eradication can cause chronic ill health, such as pulmonary impairment after tuberculosis (PIAT) and cardiovascular disease (CVD). Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Tuberculosis, Acute Coronary Syndrome, Pulmonary Hypertension (Diagnosis)
- What is being tested?
- Doxycycline
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 150 participants
- Where
- 6 sitesin 2 countries
- Study dates
- 24 May 2023to 31 Jan 2030
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Aged 21 years and above
- Patients receiving ≤ 14 days of TB treatment or about to start standard combination TB treatment
- Confirmed pulmonary TB with positive acid-fast bacilli smear and/or positive nucleic acid amplification test (NAAT) and/or TB culture results
- CXR demonstrating pulmonary involvement with cavity or cavities
- Able to provide informed consent
Who cannot join
- HIV co-infection
- Previous pulmonary TB
- Severe, pre-existing lung disease such as pulmonary fibrosis, bronchiectasis, COPD and lung cancer
- Pregnant or breast feeding
- Allergies to tetracyclines
- Patients on retinoic acid, neuromuscular blocking agents and pimozide which may increase risk of drug toxicity
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- Autoimmune disease and/or on systemic immunosuppressants
- Use of any investigational or non-registered drug, vaccine or medical device other than the study drug within 182 days preceding dosing of study drug, or planned use during the study period
- Enrolment in any other clinical trial involving a systemic drug or intervention involving the lung
- Evidence of severe depression, schizophrenia or mania
- ALT > 3 times upper limit of normal
- Creatinine > 2 times upper limit of normal
- Principal investigator assessment of lack of willingness to participate and comply with all requirements including follow-up of the protocol, or identification of any factor felt to significantly increase the participant's risk of suffering an adverse outcome
Trial locations and contacts
6 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
6 sites in 2 countries
Malaysia4 sites, 2 recruiting
- Not yet recruiting
Hospital Queen Elizabeth I
Kota Kinabalu, Sabah
Nurul Ain Mohd Yaakub, Dr, nurulainykb@moh.gov.my
Hema Yamini Devi Ramarmuty, Dr
- Active, not recruiting
Klinik Kesihatan Luyang
Kota Kinabalu, Sabah
- Recruiting
Klinik Kesihatan Menggatal
Kota Kinabalu, Sabah
Dr Siti Nor Aishah bt Abdul Rahim, +60192462367
Dr. Saravanan A/L Jayaraman, +60168040532
- Active, not recruiting
Universiti Malaysia Sabah (UMS), Borneo Medical and Health Research Centre
Kota Kinabalu, Sabah
Singapore2 sites, 2 recruiting
- Recruiting
National University Hospital
Singapore, Singapore, 119228
Catherine ONG, MRCP PhD, catherine_wm_ong@nuhs.edu.sg <catherine_wm_ong@nuhs.edu.sg>
- Recruiting
TB Control Unit
Singapore
Shera Tan, Dr, +65 6511 5131, shera_tan@ttsh.com.sg
Shera Tan, Dr
About this study
Official title: Doxycycline Host-directed Therapy to Improve Lung Function and Decrease Tissue Destruction in Pulmonary Tuberculosis: A Phase III Randomized Control Trial (Doxy-TB)
Tuberculosis (TB) is a global pandemic that despite successful treatment and bacterial eradication can cause chronic ill health, such as pulmonary impairment after tuberculosis (PIAT) and cardiovascular disease (CVD). A recent Phase 2b double-blind randomised-controlled clinical trial shows that adjunctive doxycycline therapy is safe, accelerates resolution of inflammation, suppresses tissue damaging enzyme activity and decreases pulmonary cavity volume (1). We aim to determine if adjunctive doxycycline can reduce PIAT and improve cardiovascular outcomes in a fully powered Phase III trial of 8 weeks of adjunctive doxycycline alongside standard pulmonary TB (PTB) treatment.
The investigators hypothesize that doxycycline inhibits tissue destruction in patients with PTB and thereby leads to improved lung function after treatment.
Read more
Specific aims
- To assess improvement in lung function as measured by forced expiratory volume (FEV1) predicted in PTB patients given doxycycline versus placebo.
- To investigate whether doxycycline will hasten the resolution of pulmonary cavities measured by CT thorax
- To investigate whether doxycycline can suppress inflammatory markers including matrix metalloproteinases
- To investigate whether doxycycline can accelerate time to sputum conversion
- To evaluate the effect of doxycycline on cardiovascular outcomes such as the incidence of acute coronary syndrome (ACS) and pulmonary hypertension
- To investigate whether doxycycline improves TB drug concentrations in sputum and plasma.
- To assess the safety profile of doxycycline with concurrent standard anti-tuberculous treatment.
Read the detailed description
In this Phase 3 double-blind randomised-controlled trial, doxycycline or placebo shall be given to 75 PTB patients in each arm for two months with a further follow-up of twenty-two months. Study sites are National University Hospital and TB Control Unit in Singapore and Luyang Health Clinic, Menggatal Health Clinic, and Inanam Health Clinic in Sabah, Malaysia. Lung function tests, non-contrast CT thorax, electrocardiograms and transthoracic echocardiograms will be performed at various time intervals. Induced sputum and plasma samples from all PTB patients shall be analysed for matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and monitored for sputum mycobacteria culture conversion. Whole blood will be analysed by transcriptomics for bulk RNAseq while a subset of patients' blood will be analysed using single-cell RNAsequencing. Blood tests will also be taken for Troponin-I and N-terminal pro-B-type natriuretic peptide. Accomplishing these specific aims will determine if doxycycline decreases PIAT by improving lung function, reducing pulmonary cavities and accelerating sputum culture conversion. We will also be able to assess the effect of doxycycline on development of pulmonary hypertension and acute coronary syndrome. The results will positively impact clinical practice and international guidelines including the World Health Organisation that we collaborate with, for the treatment of pulmonary TB.
- Being tested
- Doxycycline, Placebo
- Medical subject headings
- Tuberculosis, Acute Coronary Syndrome, Hypertension, Pulmonary, Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DoxycyclineDrug
A dose of 100 mg twice daily of doxycycline based on the recommended dose for adults which is commonly used for bacterial infections such as rickettsial infection, lyme disease and pelvic inflammatory disease.
PlaceboDrug
Placebo + standard anti-tuberculous treatment
| Study group | Role | What they receive |
|---|---|---|
| Doxycycline + standard anti-tuberculous treatment | Experimental | Doxycycline 100 mg twice daily with once daily anti-tuberculous treatment comprising of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 15 - 20 mg/kg, ± pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day according to managing physicians' discretion. Where needed, the drugs will be adjusted according to renal function. These will be given daily for 8 weeks. Subsequently doxycycline will be ceased and patients are to continue with their standard anti-tuberculous treatment and duration according to their managing physician Receives: Drug: Doxycycline |
| Placebo + standard anti-tuberculous treatment | Placebo comparator | Placebo twice daily with once daily anti-tuberculous treatment comprising of rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 15-20 mg/kg, ± pyrazinamide 25 mg/kg and pyridoxine 10-50 mg per day according to managing physicians' discretion. Where needed, the drugs will be adjusted according to renal function. These will be given daily for 8 weeks. Subsequently placebo will be ceased and patients are to continue with their standard anti-tuberculous treatment and duration according to their managing physician. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Forced expiratory volume in 1 second (FEV1) at 26 weeks measured by spirometry
- FEV1 at 26 weeks, expressed as a percentage predicted for age, sex, height and race will be measured by spirometry and will be compared between the doxycycline and placebo group
Measured: week 0 to 26
Secondary outcomes (15)
Forced expiratory volume in 1 second (FEV1) at 104 weeks measured by spirometry
Forced expiratory volume, expressed as a percentage predicted for age, sex, height and race will be measured by spirometry and will be compared between the doxycycline and placebo group will be measured at D0, week 8, week 26, week 52, week 78 and week 104.
Measured: 104 weeks
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio)
Forced expiratory volume in 1 second divided by forced vital capacity (FEV1/FVC ratio) measured by spirometry
Measured: 104 weeks
Safety profile
Incidence of Grade 3 or 4 adverse events and serious adverse events
Measured: week 0 to 12
Resolution of pulmonary cavities on CT scan
Proportion of patients in each study group with resolution of pulmonary cavities on CT scan done at 26, 52, 78, 104 weeks
Measured: 104 weeks
Cumulative lung cavity volume
Change in cumulative lung cavity volume (in cm3) measured on CT scan
Measured: week 0 to 104
St George's Respiratory Questionnaire Score
Change in Quality-of-life score by the St George's Respiratory Questionnaire will be measured. Scores range from 0 to 100, with higher scores indicating more limitations.
Measured: week 0 to 104
Sputum TB culture
Time taken in days for positivity of sputum TB culture using MGIT will be assessed
Measured: up to 8 weeks
Sputum culture conversion
Time taken for sputum culture conversion (time taken for sputum cultures to turn negative) by liquid cultures will be investigated
Measured: up to 8 weeks
Sputum matrix metalloproteinase (MMP) concentration
Change of sputum matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Measured: up to 8 weeks
Sputum functional assays
Change in sputum functional assays by sputum collagenase and elastase assay will be assessed.
Measured: up to 8 weeks
Host transcriptome
Change of host transcriptome will be measured via bulk RNA sequencing. In addition, in the subset of patients recruited from Singapore, single-cell RNA sequencing (scRNAseq) will be performed for neutrophils and peripheral blood mononuclear cells on 10 patients each from the doxycycline and placebo arm, analysing 10,000 cells per sample.
Measured: week 0 to 104
Host plasma matrix metalloproteinase (MMP) concentration
Change in host plasma matrix metalloproteinase (MMP) concentration will be measured by Luminex array
Measured: week 0 to 104
Pharmacokinetics and pharmacodynamics of drug concentrations
Sputum and plasma drug concentration of rifampicin, isoniazid, ethambutol, pyrazinamide (if prescribed) and doxycycline for a subset PK/PD study
Measured: week 2
Cardiac function and pulmonary hypertension
Cardiac function and pulmonary artery systolic pressure will be measured using 2D Echocardiogram and electrocardiogram at D0, week 26, week 52, week 78 and week 104. The time-to-development of pulmonary hypertension over 2 years follow-up will be calculated.
Measured: week 0 to 104
Measurement of Troponin I and NT-proBNP
HsTnI and NT-proBNP will be measured sequentially at Day 0, Week 2, 8, 26, 52, 78 and 104 to screen for cardiotoxicity, which will then be ascertained by review of source documents.
Measured: week 0 to 104
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2022
- Study start24 May 2023
- Primary completion31 Jan 2030 (estimated)
- Study completion31 Jan 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Tan Tock Seng Hospital, Hospital Queen Elizabeth, Malaysia, National University of Singapore, University Malaysia Sabah, Menggatal Health Clinic, Sabah, Malaysia, Luyang Health Clinic, Sabah, Malaysia
- Responsible party
- Sponsor
- Investigators
- Catherine Ong, MRCP PhD, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05473520
- Sponsor's protocol ID
- Phase III Doxy-TB
- Acronym
- Doxy-TB
- Status last verified
- Aug 2025
- First submitted
- 13 Jun 2022
- Last updated
- 9 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Miow QH, Vallejo AF, Wang Y, Hong JM, Bai C, Teo FS, Wang AD, Loh HR, Tan TZ, Ding Y, She HW, Gan SH, Paton NI, Lum J, Tay A, Chee CB, Tambyah PA, Polak ME, Wang YT, Singhal A, Elkington PT, Friedland JS, Ong CW. Doxycycline host-directed therapy in human pulmonary tuberculosis. J Clin Invest. 2021 Aug 2;131(15):e141895. doi: 10.1172/JCI141895.
PubMed 34128838